Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses and 1-amino-5-deoxypentofuranoses: en route to fluorinated carbanucleosides

Article abstract of DOI:10.1016/j.tet.2010.03.079

The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses and 1-amino-5-deoxypentofuranoses is described. The sequence involves an addition of PhSeCF₂TMS to carbohydrate-derived aldehydes or their corresponding tert-butanesulfinylimines followed by a radical cyclization. Optimized conditions for the PhSeCF₂TMS addition to α-chiral aldehydes have been disclosed and its unusual diastereoselectivity is discussed. Application of the sequence using Ellman's auxiliary allows a more direct access to 1-aminopentose analogues with a complete control of the pseudo-anomeric center configuration.

Full text of DOI:10.1016/j.tet.2010.03.079

Tetrahedron 66 (2010) 3963–3972
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses
and 1-amino-5-deoxypentofuranoses: en route to fluorinated carbanucleosides
`
´ ˆ
Gae¨lle Fourriere, Nathalie Van Hijfte, Jerome Lalot, Guy Dutech, Bruno Fragnet,
*
Gae¨l Coadou, Jean-Charles Quirion, Eric Leclerc
´
`
Universite et INSA de Rouen, CNRS, UMR 6014 C.O.B.R.A.–IRCOF, 1 rue Tesniere, 76821 Mont Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses and 1-amino-5-deoxy-
pentofuranoses is described. The sequence involves an addition of PhSeCF2TMS to carbohydrate-derived
aldehydes or their corresponding tert-butanesulfinylimines followed by a radical cyclization. Optimized
Received 17 November 2009
Received in revised form 25 February 2010
Accepted 22 March 2010
conditions for the PhSeCF2TMS addition to a-chiral aldehydes have been disclosed and its unusual dia-
Available online 27 March 2010
stereoselectivity is discussed. Application of the sequence using Ellman’s auxiliary allows a more direct
access to 1-aminopentose analogues with a complete control of the pseudo-anomeric center configuration.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Nucleosides
Carbasugars
Fluorine
Radical cyclization
1. Introduction
OH
X
Although being a long-standing strategy, the development of new
nucleoside analogues is still a productive approach for the de-
velopment of antitumoral or antiviral agents. Indeed, these agents
may act as inhibitors of various enzymes involved in the cell or viral
replication processes. Depending on their degree of phosphorylation,
inhibition of thymidilate synthetase, ribonucleotide reductase or
DNA polymerases may occur, these nucleoside analogues acting
either as competitive inhibitors or alternate substrates.1 Analogues
possessing a standard sugar backbone (X¼O, Fig. 1) but including
modifications either on the base or in the backbone substitutions
gave rise to several powerful anticancer or antiviral drugs (5-fluo-
rouracil, gemcitabine, azidothymidine, zalcitabine). On the other
hand, carbocyclic nucleosides (X¼CH2, Fig. 1) have acquired in recent
years a growing importance in this field, leading to the discovery of
several lead compounds (entecavir, abacavir, aristeromycin).2 Un-
fortunately, all these compounds may suffer from a lack of selectivity
or bioavailability (and thus from a certain toxicity) and the need for
new analogues with greater activities and/or lowered side effects has
therefore increased.
Base
X = O, CH2
HO
OH
Nucleosides and analogues
O
OH
N
OH
NH
O
N
NH
N
N
O
N
N3
Azidothymidine (AZT)
NH2
Abacavir
NH2
N
OH
HO
OH
NH2
O
N
N
N
N
N
O
F
Gemcitabine
OH
Aristeromycin
HO
F
Figure 1. Nucleoside and carbanucleoside drugs.
widely used as antitumoral agents. The replacement of the hydroxy
group in 2-position of the sugar backbone is also known to slow
down the metabolic cleavage of the N-glycosidic bond and gave rise
to efficient drugs (gemcitabine, clorofarabine).3 However, the syn-
thesis of CF2-carbocyclic nucleosides I, in which the intracyclic oxy-
gen atom is replaced by a CF2 group, is only scarcely described and no
general method for their preparation is provided (Scheme 1).4,5 The
strong electronegativity and the small size of the fluorine atoms
The fluorination of various positions on the base or on the pentose
backbone has been widely studied. 5-Fluorouracil (5-FU) or prodrugs
delivering 5-FU (Floxuridine, Capecitabine,.) are, for example,
* Corresponding author. Tel.: þ33 235522901; e-mail address: eric.leclerc@insa-
rouen.fr (E. Leclerc).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.079

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G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
could however impart to these surrogates better mimicking abilities
than an apolar CH2 group.3b Our current interest in the synthesis of
CF2-glycosides prompted us to devise a synthetic plan for the prep-
aration of such fluorocarbocyclic analogues of pentoses and nucleo-
sides.6 Our aim was to develop a general strategy allowing the
synthesis of II for various carbohydrate series using the same reaction
sequence. Our approach, as displayed on Scheme 1, is based on the
use of difluorocyclopentane III as the key intermediate. Compounds
of type III feature an exocyclic double bond or a phenylselanylmethyl
moiety at C-5, which would allow the introduction of the hydroxy
group. This intermediate would be obtained through a 5-exo radical
cyclization of a difluoromethyl radical onto a double or triple bond,
through an atom-transfer or reductive process. The radical precursor
IV would be readily prepared by addition of PhSeCF2TMS on the
pentose-derived aldehyde or its corresponding tert-butanesulfinyl-
imine V.
(3 equiv) and of fluoride source (3 equiv), which were first required
to complete the reaction at ꢀ78 ꢁC. These amounts were efficiently
reduced to 1.5 equiv and 1 equiv, respectively (Table 1, entry 4).
However, a mixture of the TMS ether 2 and of the free alcohol 3 is
obtained in that case.
Table 1
Optimization of the addition of PhSeCF2TMS
F
F
PhSe
OR
O
PhSeCF2TMS n equiv.
O
O
O
O
1
2 (R=TMS)
3 (R=H)
Entry
n
Conditions
2a (%)
3a (%)
drb
F
F
F
F
F F
OH
HO
1
2
3
4
1
2.5
3
TBAF 0.1 equiv, THF, ꢀ20 ꢁ
C
26
47
58
36
27
d
d
27
9:1
7:3
8:2
8:2
Y
HO
Cu(OAc)2/dppe 0.1 equiv, DMF, rt
ZH
OP
Base
OH
ZH
OP
TMAF 3 equiv, DCM, ꢀ78 ꢁC
1.5
TMAF 1 equiv, DCM, ꢀ78 ꢁ
C
PO
PO
I
II
III
TBAF¼tetrabutylammonium fluoride; dppe¼1,2-bis(diphenylphosphino)ethane;
TMAF¼tetramethylammonium fluoride.
Y = H or SePh
Z = O or NP
a
F
Isolated yields.
F
Diastereomeric ratios for 2, estimated from the 1H or 19F NMR spectra of the
PhSe
b
OH
PO
O
OH
OP
crude mixture.
Z
ZH
OP
PO
PO
OP
TMAF thus appeared as the appropriate mediator for this re-
action and we decided to apply this method to a wide range of
aldehydes obtained from various carbohydrates and diversely
protected. Aldehydes 4–9 were thus prepared using procedures
from the literature or slight modifications of the reported synthe-
ses, which always involved a Zn-promoted reductive elimination of
a carbohydrate-derived iodide as the key-step (Scheme 2).10
VI
V
IV
Scheme 1. General retrosynthetic scheme.
Our first efforts focused on the achievement of a diaster-
eoselective addition of PhSeCF2TMS to easily prepared carbohydrate-
derived aldehydes featuring an exocyclic double bond and on the
validation of our strategy through a reductive radical cyclization
leading to 5-deoxypentose analogues. First results were disclosed in
a preliminary communication and we wish to present herein a full
and detailed report of this study, which also include additional ex-
amples, the addition of PhSeCF2TMS to tert-butanesulfinylimines and
the subsequent radical cyclization of the adducts.7
OTr
1- H2SO4
1- HCl, MeOH
2- TrCl
O
D-ribose
or
D-xylose
O
OMe
2- PPh3, I2
3- NaH, BnBr
42-50%
3- Zn, MeOH
32-51%
BnO
OBn
BnO
OBn
4 or 5
O
1- CH2(OMe)2, P2O5
2. Results and discussion
2- Zn, MeOH
78%
MOMO
OMOM
6
2.1. Addition of PhSeCF2TMS to aldehydes
I
O
D-xylose
or
D-arabinose
O
OMe
1- TBSCl
1- HCl, MeOH
2- PPh3, I2
68-86%
Aldehyde 1 was prepared according to a literature procedure
2- Zn, MeOH
64%
TBSO
BzO
OTBS
involving a Zn-promoted reductive elimination of a D-ribose-derived
HO
OH
iodide.8 The addition of PhSeCF2TMS to this substrate was examined
using various conditions reported in the literature (Table 1). If the
fluoride-promoted addition of PhSeCF2TMS to aromatic aldehydes is
7
O
1- PhCOCl
well established,9 the use of easily enolizable
a-chiral aldehydes is
2- Zn, vitamin B12
57%
OBz
poorly documented. Our first attempts were direct applications of
the method described by Qing using a catalytic amount of TBAF in
THF.9a If addition products 2 and 3 were indeed isolated using this
method (Table 1, entry 1), a significant amount of by-products
resulting from the base-promoted enolization of the aldehyde
were also detected. Lowering the reaction temperature or the
amount of TBAF did not improve this result. We thus turned our
attention to a Lewis acid-based method, which was recently repor-
ted.9d The use of Cu(OAc)2/dppe as an activator indeed allowed us to
isolate 2 as the sole product, but in moderate yield and diaster-
eoselectivity (Table 1, entry 2). The use of TMAF as the promoter in
CH2Cl2 at low temperature eventually led to 2 in higher yield and
with an acceptable diastereoselectivity (Table 1, entry 3).9c No by-
products were detected despite the large excess of nucleophile
8
Scheme 2. Preparation of aldehydes 4–9.
The addition of PhSeCF2TMS was then examined on each of these
substrates. The use of only a slight excess of reagents requires a two-
step procedure to convert the isolated OH/OTMS mixture to the free
alcohol 3 (Scheme 3). Worthy of note is the fact that, for benzyl- or
MOM-protected aldehydes such as 4–6, a warm-up to rt is sufficient
to afford alcohols 10–12 in high yield. The TBS-protected arabinose
derivative 7 led to the fully deprotected addition product 13 in ap-
preciable yield thanks to the two-step procedure mentioned earlier.
One exception to the TMAF-mediated reaction is the benzoyl-
protected arabinose derivative 8. The addition product 14 could

G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
3965
indeed be isolated only in low yield and using TBAT as the fluoride
source (Scheme 3), indicating that the electrophilicity of such pro-
tecting groups was inappropriate in this reaction. Finally, the
glucose-derived aldehyde 9 could be also converted to alcohol 15
thanks to the two-step procedure.11 Diastereomeric ratios
(estimated from 1H or 19F NMR spectra of the crude mixture) were
always in the 80:20 range, except for the TBS-protected aldehyde 7
for which an almost complete diastereoselectivity is observed. The
relative configuration of each major diastereomer, which is dis-
played on Scheme 2 was not determined at that stage.
of the substrate was ever observed, which could have explained the
moderate yields obtained for 21, 22, and 24. The reaction conditions
appeared compatible with all the protecting groups, which were
tested (esters, ethers, and acetonide). Not surprisingly, the cautious
acetylation of the free hydroxy groups from 3, 11, 13, and 14 proved
unnecessary, as illustrated by the successful cyclization of the un-
protected arabinose derivative 13 (Scheme 4). The diaster-
eoselectivity of the reaction (estimated from 1H or 19F NMR spectra
of the crude mixture) is strongly dependant on the substrate (vide
infra). Finally, a 6-exo-trig radical cyclization of compound 15 was
also attempted but the cyclized compound was obtained only in low
yield and with a low purity.
F
F
PhSe
1. PhSeCF2TMS 1.5 equiv.
OH
O
TMAF 1 equiv., CH2Cl2, -78°C
2. TBAF, THF, rt
F
F
F
F F
F
O
O
O
O
PhSe
O
48%, dr = 80:20
OAc
OAc
(n-Bu)3SnH, AIBN
OAc
+
1
t-BuOH, 80°C
3
89%, dr = 1:1
O
O
O
O
O
F
F
PhSe
BnO
PhSeCF2TMS 1.5 equiv.
TMAF 1 equiv., CH2Cl2
20b
20a
16
O
OH
F
F
F
F
-78°C to rt
77%, dr = 80:20
PhSe
BnO
OBn
OBn
OAc
OBn
(n-Bu)3SnH, AIBN
OAc
4
10
t-BuOH, 80°C
F
48%, dr = 9:1
BnO
BnO
OBn
F
17
21
PhSe
BnO
PhSeCF2TMS 1.5 equiv.
TMAF 1 equiv., CH2Cl2
F
OH
O
F
F
F
PhSe
(n-Bu)3SnH, AIBN
t-BuOH, 80°C
43%, dr = 8:2
-78°C to rt
78%, dr = 80:20
OAc
OBz
BnO
MOMO
TBSO
BzO
OBn
OBn
OAc
11
5
F
BzO
OBz
BzO
22
F
18
PhSe
PhSeCF2TMS 1.5 equiv.
TMAF 1 equiv., CH2Cl2
F
OH
O
F
F
F
PhSe
(n-Bu)3SnH, AIBN
t-BuOH, 80°C
70%, dr = 9:1
OAc
OAc
-78°C to rt
75%, dr = 80:20
OAc
OMOM
MOMO
OMOM
12
6
AcO
AcO
OAc
F
19
23
F
PhSe
HO
F
1. PhSeCF2TMS 1.5 equiv.
F
F
F
OH
O
TMAF 1 equiv., CH2Cl2, -78°C
PhSe
(n-Bu)3SnH, AIBN
OH
OH
2. TBAF, THF, rt
59%, dr =95:05
OH
OH
OTBS
OH
t-BuOH, 80°C
13
7
52%, dr = 9:1
HO
HO
F
24
13
F
PhSe
1. PhSeCF2TMS 3 equiv.
Me
O
Me
Me
OH
O
TBAT 1.5 equiv., THF, -78°C
O
O
F
AcO
F
OBn
F
O
O
H
Me
F
F
F
O
H
2. TBAF, THF, rt
27%, dr =75:25
H
O
H
Me
H
H
H
O
OBz
BzO
OBz
H
F
H
14
8
F
Me
H
Me
H
H
H
F
F
H
O
O
O
H
BnO
OAc
H
O
1. PhSeCF2TMS 1.5 equiv.
PhSe
O
OH
TMAF 1 equiv., CH2Cl2, -78°C
2. TBAF, THF, rt
20a
20b
21
23
BnO
OBn
BnO
OBn
OBn
15
64%, dr = 80:20
OBn
9
Scheme 4. Synthesis of the 5-deoxypentose CF2-carbocyclic analogues.
Scheme 3. Addition of PhSeCF2TMS under optimized conditions.
Compound 21 was deacetylated and subjected to a Mitsunobu
reaction using N3-benzoylthymine as the nucleophile.4d Disap-
pointingly, the expected pseudo-nucleoside could not be obtained
from this reaction on a sterically hindered substrate.
2.2. Radical cyclization
Having in hands several precursors, we then investigated the
crucial 5-exo-trig radical cyclization. A classical, reductive tin
hydride-mediated cyclization was first performed as it would allow
us to demonstrate our synthetic strategy.4a,4b,12 Moreover, the
5-deoxypentose analogues, which would be obtained from such
a reaction, if less valuable than the exact analogues, remain in-
teresting original structures with only few precedents in the liter-
ature. Compounds 3, 11, 13, and 14 obtained from the addition
reactions were thus acetylated and engaged in reductive radical
cyclizations (Scheme 4). Complete conversion of the starting ma-
terial was generally observed within 2 h and cyclized compounds
20–24 were obtained in moderate to highyields. No direct reduction
2.3. Stereochemical outcome of the addition and cyclization
reactions
The relative configurations of the cyclized compounds 20, 21,
and 23 were easily determined thanks to NOESY NMR experiments
and the configuration of 22 and 24 was deduced from these results
(Scheme 4: the colored arrows stand for the observed NOESY cor-
relations). This work provided answers to the stereochemical out-
come of both the PhSeCF2TMS addition and the radical cyclization.
The latter proceeds according to the well-known Beckwith–Houk

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G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
transition state.13 A strong diastereoselectivity was therefore ob-
served in the reaction of the xylose and arabinose derivatives 17
and 19 for which an ‘all equatorial’ transition state is possible
(Scheme 5). On the other hand, an equimolar mixture of the two
the 1H and 19F NMR spectra of the crude mixture). It has been
unambiguously demonstrated, thanks to simple hydrolytic
cleavage of the sulfinamide group, that the C-2 configuration of
each major diastereomer was exclusively controlled by the chiral
a
F
F
F
F
F
.
BnO
F
.
OAc
OAc
O
OAc
BnO
AcO
20a
21
AcO
O
F
F
F
O
O
O
O
BnO
OBn
vs
17
16
vs
F
F
OBn
OAc
F
F
OAc
OAc
OBn
O
.
.
F
20b
BnO
O
F
OBn
One TS free of 1,3-diaxial interactions
Scheme 5. Stereoselectivity of the radical cyclization.
F
dr = 1:1
1,3-diaxial interactions in both TS
dr = 9:1
C-5 epimers 20a and 20b was obtained from the ribose derivative
16. Both transition states leading to these compounds indeed suffer
from at least one non-bonding 1,3-diaxial interaction (Scheme 5).
The stereochemical outcome of the addition of PhSeCF2TMS to
aldehydes 1 and 4–9 was less expected. anti-Felkin adducts are in-
deed obtained as the major diastereomers whereas the addition of
fluoroalkylsilane reagents to
stereoselective except for
a
-chiral aldehydes is often poorly dia-
a-dibenzylaminoaldehydes for which
a Felkin selectivity is observed.14 If a chelated transition state can be
considered for the reactions promoted by Cu(OAc)2 and dppe (Table 1,
entry 2), such a model is irrelevant regarding the fluoride-promoted
additions. However, Portella’s group observed similar results in the
addition of fluoroalkylsilane reagents to other highly functionalized
carbohydrate-derived aldehydes.15 These authors suggested that the
unusual bulkyness of the postulated hypervalent fluorosilicon in-
termediate and of the electrophile could give rise to non-classical
transition states. The models grounded on stabilizing hyper-
conjugation, either from the Anh/Eisentein or Cieplak interpretation,
imply conformations, which might indeed be disfavored due to the
steric hindrance of both partners (Fig. 2).16 Two transition states are
therefore proposed, which account for the observed selectivity and
allow the minimization of steric interactions (Fig. 2). A is a Felkin
model in which the bulky substituent takes the place of the elec-
tronegative one.17 This conformation has been determined to be the
most stable one from an energy minimization study of aldehyde 7
performed using the Discover/Insight II software (Fig. 2). However,
reasoning on the most stable conformation of the substrate might be
misleading for reactions on highly flexible aldehydes. Alternatively,
transition state B, which is similar to the one proposed by Portella,
clearly minimizes the steric hindrance despite an unusual gauche
conformation. Moreover, the relative orientations of the C–OR bond
and the incoming nucleophile offer supplemental stabilization
thanks to dipole moment minimization.18
Figure 2. Diastereoselectivity of the PhSeCF2TMS addition.
auxiliary. Indeed, acetamides 28 and 32 displayed different 1H, 13C,
and 19F NMR data, indicating they were diastereomers, which could
only differ by their C-2 configuration. Moreover, the observed
match/mismatch cases were in agreement with what could be
predicted from the literature.12f,19 Indeed, the stereochemical out-
come of nucleophilic additions using this chiral auxiliary is well
established and, when confronted to the selectivity that we pre-
viously observed for the corresponding aldehydes, implies
a matched diastereoselectivity for 30. The reductive radical cycli-
zation of addition products 27 and 31 afforded the corresponding
5-deoxypentofuranose analogues 29 and 33 in good yield. The
relative configuration of 29 was again determined thanks to NOESY
correlations and the predicted stereoselectivity for the PhSeCF2TMS
addition was thus confirmed. Signal overlaps in the 1H NMR spec-
trum of 33 did not allow us to draw conclusions from NOESY ex-
periments. However, if the change of C-2 configuration is admitted,
2.4. Addition of PhSeCF2TMS to tert-butanesulfinylimines
and cyclization
In order to provide a more direct access to nucleoside analogues
and to control at will the configuration of the pseudo-anomeric
center, a similar sequence was performed on tert-butanesulfinyl-
imines 26 and 30 (Scheme 6). The addition of PhSeCF2TMS pro-
ceeded smoothly according to the procedure developed by Hu,
using TBAT as a promoter.12f A mismatched diastereoselectivity
(dr¼83:17) was observed in the case of 26 and the matched case
was obtained for 30 (dr >98:02, only one diastereomer detected in

G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
3967
O
O
F
F
F F
S
PhSe
BnO
S
PhSe
BnO
PhSeCF2TMS 2.4 equiv.
TBAT 1 equiv.
N
NH
OBn
NHAc
OBn
1- HCl, MeOH
2- Ac2O
90%
DMF, -40°C
BnO
OBn
O
52%, dr = 83:17
26
27
28
S
(n-Bu)3SnH, AIBN
t-BuOH, 80°C
H2N
Ti(OEt)4
85%
F
72%, dr = 59:41
NHS(O)t-Bu
Me
H
BnO
F
O
O
F
F
S
H
H
OBn H
NH
BnO
OBn
25
BnO
OBn
29
Ti(OEt)4
81%
O
S
H2N
O
O
F
F
F
F
S
PhSe
PhSe
BnO
S
PhSeCF2TMS 2.4 equiv.
TBAT 1 equiv.
N
NHAc
OBn
32
NH
1- HCl, MeOH
2- Ac2O
DMF, -40°C
72%, dr > 98:02
BnO
OBn
BnO
OBn
30
85%
31
(n-Bu)3SnH, AIBN
t-BuOH, 80°C
78%, dr = 90:10
O
F
F
S
NH
BnO
OBn
33
Scheme 6. Addition to sulfinylimines and cyclization.
the depicted relative configuration for 33 can be deduced from the
high selectivity of the radical cyclization. Indeed, in that case,
a transition state placing all substituents in pseudo-equatorial po-
sition is possible, leading to 33 with the represented C-5 configu-
ration. This assumption is confirmed by the low diastereoselectivity
obtained for the cyclization of 27, in which the C-2 configuration
requires to place at least one substituent in pseudo-axial position
for both possible transition states.
An attempt was made to convert compound 33 to the corre-
sponding pyrimidyl nucleoside using a known procedure.4c After
cleavage of the sulfinyl auxiliary, the free amine function was
allowed to react with 3-ethoxy-2-propenoyl isocyanate. Un-
fortunately, no reaction occurred, which might be due to the steric
hindrance and weak nucleophilicity of this substrate.
These strategies are currently under investigation and results in
this area will be reported in due course.
4. Experimental
4.1. General
All reactions were carried out under an argon atmosphere with
dry solvents under anhydrous conditions, unless otherwise noted.
Dry THF, DMF, or CH2Cl2 were obtained by drying over Na/benzo-
phenone (THF) or barium oxide (DMF) or P2O5 (CH2Cl2) and distil-
lation. All reagents were purchased from commercial sources and
used without further purification. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm silica gel
plates using UV light as a visualizing agent and an ethanolic solution
of phosphomolybdic acid, p-anisaldehyde or potassium permanga-
nate, and heat as developing agents. Chromatographic purifications
were carried out using silica gel columns (60, particle size 0.040–
0.063 mm or 0.070–0.200 mm) or automated equipment with pre-
packed silica cartridges. 1H NMR, 13C NMR, and 19F NMR spectra
were recorded on a 300 MHz instrument and calibrated using re-
sidual undeuterated solvent as an internal reference. The NOESY
experiments were recorded on a 400 or 500 MHz instrument. The
following abbreviations were used to explain the multiplicities:
s¼singlet, d¼doublet, t¼triplet, q¼quadruplet, m¼multiplet,
app¼apparent. Mass spectrometry (MS) experiments were per-
formed using electrospray ionization (ESI). IR spectra were recorded
on an FT-IR spectrometer. Optical rotations were measured at 20 ꢁC
3. Conclusion
An efficient preparation of difluorinated carbocyclic 5-deoxy-
pentofuranose and 1-amino-5-deoxypentofuranose analogues has
thus been carried out. The synthetic pathway involves an addition
of PhSeCF2TMS to carbohydrate-derived aldehydes or tert-butane-
sulfinylimines featuring a terminal double bond followed by a re-
ductive 5-exo-trig radical cyclization. The PhSeCF2TMS addition
exhibited an interesting, though unusual, diastereoselectivity and
the use of Ellman’s auxiliary appeared to be the method of choice
for a rapid access to 1-aminopentose analogues with a total control
of the pseudo-anomeric center. An efficient method for a future
synthesis of pentofuranose and nucleoside surrogates has been
secured thanks to this study. Indeed, performing a similar sequence
using a phenylselanyl group transfer radical cyclization with the
same substrates or a reductive 5-exo-dig radical cyclization of
similar precursors featuring a terminal triple bond should allow us
to achieve this goal. More work devoted to the conversion of the
carbasugars to nucleoside analogues should also be performed.
and with
l
¼589 nm; concentrations are expressed in cg mLꢀ1
.
4.2. (2S,3R,4R)-3,4-O-Isopropylidene-1,1-difluoro-1-
phenylselanyl-hex-5-en-2,3,4-triol (3)
To a solution of aldehyde 1 (1.11 g, 3.74 mmol) and PhSeCF2TMS
(1.57 g, 5.60 mmol, 1.5 equiv), with suspended MS 4 Å, in dry

3968
G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
CH2Cl2 (20 mL) at ꢀ78 ꢁC was added TMAF (350 mg, 3.74 mmol,
1 equiv). The reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h.
Water was then added and the aqueous layer was extracted with
CH2Cl2. The combined organic layers were then washed with brine,
dried over MgSO4, filtered, and concentrated under reduced pres-
sure. The crude residue was then purified by flash chromatography
using cyclohexane/AcOEt (97:3) as eluent to afford the desired
addition product as its TMS ether (1.62 g, 63%). To a solution of this
mixture of diastereomers (400 mg, 0.92 mmol) in dry THF was
added a solution of TBAF (1 M in THF, 1.1 mL,1.2 equiv). The mixture
was then stirred at rt for 1 h. Water was then added and the
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude residue was then purified by flash
chromatography using cyclohexane/AcOEt (95:05 then 90:10) as
eluent to afford the separated (2S,3R,4R) (3) and (2R,3R,4R) dia-
stereomers (215 mg and 40 mg, respectively, 76% overall) as yellow
NMR (75.5 MHz, CDCl3) d 138.3, 137.8, 137.6, 134.5, 129.6, 129.3,
128.6 (ꢂ2), 128.2, 128.0, 127.9, 127.7, 127.6 (t, J¼298.9 Hz), 124.1,
121.0, 81.8, 76.9 (d, J¼1.7 Hz), 74.9, 72.7 (t, J¼23.9 Hz), 70.9. IR (neat)
nmax 3521, 3063, 3032, 2870, 1579 cmꢀ1. MS (ESIþ): m/z¼522.1
([MþH2O]þ). HRMS (CIþ) calcd for C26H27F2O3Se ([MþH]þ) m/z
505.1094, found 505.1093.
4.5. (2S,3R,4S)-3,4-Bis(O-methoxymethyl)-1,1-difluoro-1-
phenylselanyl-hex-5-en-2,3,4-triol (12)
The same procedure was applied to 6 (0.885 g, 4.3 mmol). Purifi-
cation by column chromatography (10% EtOAc in cyclohexane)
afforded the pure (2S,3R,4S) diastereomer (12) and a mixture of the
(2S,3R,4S) and (2R,3R,4S) diastereomers (1.341 goverall, 75%). Rf¼0.33
(20%AcOEt incyclohexane).1H NMR (300 MHz, CDCl3)
d 7.52–7.48 (m,
2H), 7.21–7.12 (3H, m), 5.62 (ddd, J¼16.7, 10.3, 7.8 Hz, 1H), 5.17–5.08
(m, 2H), 4.61–4.34 (m, 8H), 4.07–4.01 (m, 1H), 3.98–3.86 (m, 1H),
3.82–3.78 (m, 1H), 3.21 (s, 3H), 3.12 (s, 3H). 19F NMR (282.5 MHz,
oils. Rf¼0.52 (20% AcOEt in cyclohexane). [
a
]
D þ3.4 (c 1.1, CHCl3). 1H
NMR (300 MHz, CDCl3)
d
7.72 (d, 2H, Ar), 7.44–7.30 (m, 3H), 5.94
CDCl3)
d
ꢀ77.7 (dd, J¼207.7, 6.9 Hz, 1F), ꢀ84.2 (dd, J¼207.7, 17.2 Hz,
(ddd, J¼17.8, 10.1, 8.1 Hz, 1H), 5.40–5.27 (m, 2H), 4.71 (t, J¼7.9 Hz,
1H), 4.51 (d, J¼7.5 Hz, 1H), 3.85 (dt, J¼14.9, 8.8 Hz, 1H), 3.07 (d,
J¼9.7 Hz, 1H), 1.56 (s, 3H), 1.40 (s, 3H). 19F NMR (282.5 MHz, CDCl3)
1F). 13C NMR (75.5 MHz, CDCl3)
d
137.6, 134.0, 129.3, 127.5 (t,
J¼298.9 Hz), 120.1, 98.2, 94.3, 77.6, 75.7, 72.2 (dd, J¼26.1, 22.7 Hz),
56.8, 55.9. MS (ESIþ): m/z¼435.1 ([MþNa]þ). Anal. Calcd for
C16H22F2O5Se: C, 46.72; H, 5.39. Found: C, 46.68; H, 5.38.
d
ꢀ79.1 (dd, J¼210.1, 8.0 Hz, 1F), ꢀ82.2 (dd, J¼210.5, 15.1 Hz, 1F). 13
C
NMR (75.5 MHz, CDCl3)
d 137.6, 133.9, 129.7, 129.4, 127.3
(t, J¼300.7 Hz), 124.0, 120.9, 109.8, 79.7, 74.4 (d, J¼3.4 Hz), 72.2
(t, J¼24.7 Hz), 26.9, 24.7. IR (neat) nmax 3411, 3060, 2988, 2924, 2851,
1713, 1580 cmꢀ1. MS (ESIþ): m/z¼381.93 ([MþH2O]þ). Anal. Calcd
for C15H18F2O3Se: C, 49.60; H, 4.99. Found: C, 49.39; H, 4.78.
4.6. (2R,3S,4R)-1,1-Difluoro-1-phenylselanyl-hex-5-ene-2,3,4-
triol (13)
To a solution of aldehyde 7 (1.69 g, 4.9 mmol) and PhSeCF2TMS
(2.06 g, 7.40 mmol,1.5 equiv), with suspended MS 4 Å, in dry CH2Cl2
(150 mL) at ꢀ78 ꢁC was added TMAF (459 mg, 4.90 mmol, 1 equiv).
The reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h. Water
was then added and the aqueous layer was extracted with CH2Cl2.
The collected organics were then washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. To a so-
lution of the obtained crude residue in dry THF (20 mL) was added
a solution of TBAF (1 M in THF, 12.3 mL, 5 equiv). The mixture was
stirred at rt for 1 h and water was added. The aqueous phase was
extracted with CH2Cl2 and organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude resi-
due was then purified by flash column chromatography using
CH2Cl2/MeOH (99:1) as eluent to afford the pure (2R,3S,4R) dia-
stereomer 13 and a mixture of the (2R,3S,4R) and (2S,3S,4R) dia-
stereomers (146 mg and 233 mg, respectively, 59% over two steps)
4.3. (2S,3R,4R)-3,4-Bis(O-benzyl)-1,1-difluoro-1-
phenylselanyl-hex-5-en-2,3,4-triol (10)
To a solution of aldehyde 4 (1.11 g, 3.74 mmol) and PhSeCF2TMS
(1.57 g, 5.60 mmol, 1.5 equiv), with suspended MS 4 Å, in dry
CH2Cl2 (20 mL) at ꢀ78 ꢁC was added TMAF (350 mg, 3.74 mmol,
1 equiv). The reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h
30 min, warmed up to ꢀ40 ꢁC for 1 h and then to rt for 1 h. Water
was then added and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifi-
cation by flash column chromatography using cyclohexane/AcOEt
(98:2) as eluent afforded the pure (2S,3R,4R) diastereomer 10 and
a mixture of the (2S,3R,4R) and (2R,3R,4R) diastereomers (1.460 g
overall, 77%). 1H NMR (300 MHz, CDCl3)
d
7.75 (d, 2H), 7.35 (m,13H),
as white solids. Rf¼0.36 (4% MeOH in CH2Cl2). [
a
]
ꢀ9.9 (c 1.2,
D
5.87 (ddd, 1H, J¼16.5, 11.0, 7.3 Hz), 5.43 (m, 2H), 4.66 (m, 3H), 4.38
CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.69 (d, J¼7.78 Hz, 2H), 7.45–
(d, 1H), 4.21 (m, 1H), 3.99 (t, 1H, J¼7.3 Hz), 3.88 (d, 1H, J¼7.0 Hz),
7.31 (m, 3H), 5.81 (ddd, J¼17.4, 10.4, 7.0 Hz, 1H), 5.35 (d, J¼32.2 Hz,
1H), 5.30 (d, J¼25.4 Hz, 2H), 4.25–4.11 (m,1H), 3.91 (d, J¼6.7 Hz, 2H),
3.71 (br s, 1H), 3.34 (br s, 1H), 2.99 (br s, 1H). 19F NMR (282.5 MHz,
3.36 (d, 1H, J¼9.5 Hz). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ76.68
(dd, J¼215.8, 10.3 Hz), ꢀ78.55 (dd, J¼215.7, 11.5 Hz). 13C NMR
(75.5 MHz, CDCl3)
(d, J¼2.3 Hz), 120.8, 80.3, 77.6 (d, J¼2.2 Hz), 74.4, 72.8 (dd, J¼23.0,
d
137.7, 135.3, 128.5, 127.7 (t, J¼299.7 Hz), 124.2
CDCl3)
d
ꢀ78.7 (dd, J¼211.2,10.4 Hz,1F), ꢀ81.9 (dd, J¼213.3,14.5 Hz,
1F). 13C NMR (75.5 MHz, CDCl3)
d
137.7, 136.1, 135.9, 129.9, 129.5,
3.0 Hz), 70.9. MS (ESIþ): m/z¼522.1 ([MþH2O]þ).
127.3 (t, J¼300.5 Hz), 123.9, 120.6, 119.9, 74.6, 73.6 (t, J¼24.6 Hz),
70.9 (d, J¼2.4 Hz). IR (neat) nmax 3504, 3154, 2844, 1955, 1881, 1646,
4.4. (2S,3R,4S)-3,4-Bis(O-benzyl)-1,1-difluoro-1-
phenylselanyl-hex-5-en-2,3,4-triol (11)
1580 cmꢀ1
.
GC–MS: m/z¼341.9 ([MþH2O]þ). Anal. Calcd for
C12H14F2O3Se: C, 44.59; H, 4.37. Found: C, 44.77; H, 4.25.
The same procedure was applied to 5 (1.1 g, 3.7 mmol). Purifi-
cation by flash column chromatography using cyclohexane/AcOEt
(98:2 then 95:5) as eluent afforded the pure (2S,3R,4S) (11) and the
pure (2R,3R,4S) diastereomers, and a mixture of both (1 g, 155 mg
and 310 mg, respectively, 78% overall) as colorless oils. Rf¼0.25
4.7. (2R,3S,4R)-3,4-Bis(O-benzoyl)-1,1-difluoro-1-
phenylselanyl-hex-5-en-2,3,4-triol (14)
To a solution of aldehyde 8 (1.75 g, 5.40 mmol) and PhSeCF2TMS
(4.52 g, 16.19 mmol, 3 equiv), with suspended MS 4 Å, in dry THF
(200 mL) at ꢀ78 ꢁC was added TBAT (4.37 g, 8.10 mmol, 1.5 equiv).
The reaction mixture was allowed to stir at ꢀ78 ꢁC for 1 h. Water
was then added and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were then washed with brine, dried
over MgSO4, filtered, and concentrated under reduced pressure. To
a solution of this crude product in dry THF (30 mL) was added
(5% AcOEt in cyclohexane). [
(300 MHz, CDCl3)
a
]
D
ꢀ14.4 (c 1.1, CHCl3). 1H NMR
d
7.84 (d, J¼7.1 Hz, 2H), 7.62–7.37 (m, 13H), 5.90
(ddd, J¼16.4, 11.3, 7.7 Hz, 1H), 5.51 (s, 1H), 5.44 (d, J¼7.0 Hz, 1H),
4.90 (dd, J¼48.1, 10.4 Hz, 2H), 4.61 (dd, J¼66.2, 11.9 Hz, 1H), 4.28–
4.06 (m, 3H), 3.50 (d, J¼10.1 Hz, 1H). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ79.9 (dd, J¼208.8, 7.5 Hz,1F), ꢀ83.1 (dd, J¼208.8,15.5 Hz,1F). 13
C

G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
3969
a solution of TBAF (1 M in THF, 2.6 mL, 1.2 equiv) and the mixture
was stirred at rt for 1 h. Water was then added and the aqueous
layer was extracted with CH2Cl2. The organic phase was dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude residue was then purified by flash chromatography using
cyclohexane/AcOEt (95:5 then 9:1) as eluent to afford the pure
(2R,3S,4R) (14) and the pure (2S,3S,4R) diastereomers and a mixture
of both (384 mg, 17 mg and 200 mg, respectively, 27% overall, over
two steps) as pale orange solids. Rf¼0.16 (10% EtOAc in cyclohex-
(c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3)
d
5.12 (d, J¼9.4 Hz, 1H), 4.62
(dt, J¼6.4, 4.5 Hz, 1H), 4.45 (dd, J¼6.4, 4.5 Hz, 1H), 2.53–2.32 (m, 1H),
2.11 (s, 3H), 1.46 (s, 3H), 1.29 (s, 3H), 1.18 (d, J¼7.0 Hz, 3H). 19F NMR
(282.5 MHz, CDCl3)
d
ꢀ112.5 (ddd, J¼245, 25.3, 9.3 Hz, 1F), ꢀ115.8
(dq, J¼246.2, 4.3 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d 169.1, 126.4
(dd, J¼262.6, 256.6 Hz), 111.9, 81.3 (d, J¼4.4 Hz), 78.4 (d, J¼11.5 Hz),
76.5 (dd, J¼36.2, 19.2 Hz), 41.9 (t, J¼21.9 Hz), 26.1, 24.4, 21.0, 5.8
(d, J¼4.4 Hz). MS (ESIþ): m/z¼268.2 ([MþH2O]þ).
ane). [
a]
þ39.9 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.95
4.10. (2S,3R,4S,5S)-2-O-Acetyl-3,4-bis(O-benzyl)-1,1-difluoro-
5-methylcyclopentane-2,3,4-triol (21)
D
(q, J¼7.4 Hz, 4H), 7.67 (d, J¼7.4 Hz, 2H), 7.53–7.48 (m, 2H), 7.43–7.29
(m, 7H), 5.97–5.85 (m, 3H), 5.57 (d, J¼17.4 Hz,1H), 5.40 (d, J¼9.9 Hz,
1H), 4.28 (dt, J¼16.9, 8.6 Hz, 1H), 3.15 (d, J¼10.1 Hz, 1H). 19F NMR
The same procedure was applied to 17 (50 mg; 0.09 mmol). Pu-
rification by column chromatography using cyclohexane/AcOEt
(97:3) as eluent afforded the desired product (17 mg, 48%) as a col-
orless oil. Only the major (2S,3R,4S,5S) diastereomer 21 was isolated.
(282.5 MHz, CDCl3)
d
ꢀ79.4 (dd, J¼213.2, 8.2 Hz, 1F), ꢀ83.8
(dd, J¼215.7, 14.1 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d 165.7, 165.4,
137.7, 133.7, 133.5, 131.8, 130.0, 129.7, 129.6, 129.5, 128.7 (2C), 126.5
(t, J¼300.3 Hz), 123.5, 122.3, 74.5, 73.0 (t, J¼25.4 Hz), 70.7. IR (neat)
nmax 3475, 3063, 1733, 1713, 1601 cmꢀ1. MS (ESIþ): m/z¼549.93
([MþH2O]þ). Anal. Calcd for C26H22F2O5Se: C, 58.76; H, 4.17. Found:
C, 58.80; H, 4.13.
Rf¼0.14 (5% EtOAc in cyclohexane). [
a
]
D þ8.8 (c 1.5, CHCl3). 1H NMR
(300 MHz, CDCl3)
d
7.41–7.24 (m, 10H), 5.18 (dt, J¼12.9, 2.7 Hz, 1H),
4.74–4.55 (m, 4H), 3.92 (dt, J¼5.3, 3.8 Hz, 1H), 3.60 (ddd, J¼9.8, 5.5,
1.5 Hz, 1H), 2.48–2.26 (m, 1H), 2.14 (s, 3H), 1.18 (d, J¼6.8 Hz, 3H). 19F
NMR (282.5 MHz, CDCl3)
d
ꢀ111.7 (ddd, J¼242.7, 13.1, 10.1 Hz, 1F),
4.8. (2S,3R,4S,5R)-3,4,5-Bis(O-benzyl)-1,1-difluoro-1-
phenylselanyl-hept-6-en-2,3,4-tetraol (15)
ꢀ113.5 (ddt, J¼243.2, 11.0, 3.2 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d 169.6, 138.1, 137.6, 128.8, 128.7, 128.4, 128.3, 128.2, 128.1, 123.0
(dd, J¼263.8, 251.7 Hz), 86.3 (d, J¼2.3 Hz), 84.7 (d, J¼8.6 Hz), 76.3
(dd, J¼35.6, 19.5 Hz), 73.1, 72.6, 43.4 (t, J¼21.8 Hz), 21.0, 9.3
(d, J¼5.2 Hz). IR (neat) nmax 2884, 1755 cmꢀ1. MS (ESIþ): m/z¼452.3
([MþH2Oþ2Naþ2H]þ), 426.2 ([Mþ2H2O]þ), 408.2 ([MþH2O]þ).
Anal. Calcd for C22H24F2O4: C, 67.68; H, 6.20. Found: C, 67.45; H, 6.22.
The same two-step procedure used for 1 was applied to aldehyde
9. Purification by flash column chromatography using cyclohexane/
AcOEt (98:2 then 95:5) as eluent afforded the major (2S,3R,4S,5R)
diastereomer 15 and a mixture of the (2S,3R,4S,5R) and (2R,3R,4S,5R)
diastereomers (63% yield overall). Rf¼0.29 (10% AcOEt in cyclohex-
ane). 1H NMR (300 MHz, CDCl3)
d
7.72 (d, J¼7.0 Hz, 2H), 7.32–7.21
4.11. (2R,3S,4R,5R)-2-O-Acetyl-3,4-bis(O-benzoyl)-1,1-
difluoro-5-methylcyclopentane-2,3,4-triol (22)
(m, 28H), 5.89 (ddd, J¼17.5, 10.6, 7.2 Hz, 1H), 5.27 (m, 2H), 4.76–4.57
(m, 5H), 4.34 (d, J¼11.9 Hz, 1H), 4.15–3.95 (m, 3H), 3.38 (d, J¼9.4 Hz,
1H). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ77.5 (dd, J¼207.3, 6.2 Hz, 1F),
The same procedure was applied to 18 (57 mg; 0.10 mmol).
Purification by column chromatography using cyclohexane/AcOEt
(95:5 then 9:1) as eluent afforded the desired product (18 mg, 43%)
as a pale yellow oil and as a mixture of diastereomers. Only the
analytical data of the major (2R,3S,4R,5R) diastereomer 22 are
provided. Rf¼0.27 (10% EtOAc in cyclohexane). 1H NMR (300 MHz,
ꢀ82.8 (dd, J¼207.3,16.5 Hz).13C NMR (75.5 MHz, CDCl3)
d 137.9, 137.7,
137.5, 137.3 (2C); 134.71, 129.3–127.7 (m, 7C), 127.3 (t, J¼300.0 Hz);
118.9, 81.4, 79.1, 75.6 (d, J¼2.7 Hz), 74.9, 74.5 (2C), 72.5 (t, J¼25.0 Hz),
70.4. MS (ESIþ): m/z¼642.20 ([MþH2O]þ). Anal. Calcd for
C26H22F2O5Se: C, 65.49; H, 5.50. Found: C, 65.51; H, 5.46.
CDCl3)
d 8.10–8.01 (m, 4H), 7.63–7.55 (m, 2H), 7.52–7.38 (m, 4H),
4.9. (2S,3R,4R,5R)- and (2S,3R,4R,5S)-2-O-Acetyl-3,4-O-
isopropylidene-1,1-difluoro-5-methylcyclopentane-2,3,4-triol
(20a and 20b)
5.62–5.57 (m, 1.5H), 5.48–5.37 (m, 1.5H), 2.80–2.60 (m, 1H), 2.20 (s,
3H), 1.30 (d, J¼7.1 Hz, 3H). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ111.4
(ddd, J¼243.1, 18.4, 11.7 Hz, 1F), ꢀ112.5 (ddq, J¼243.2, 13.4, 2.1 Hz,
1F). 13C NMR (75.5 MHz, CDCl3)
d 169.4, 166.0, 165.8, 133.9, 133.8,
To a solution of 16 (324 mg, 0.80 mmol) in t-BuOH (28 mL) was
added AIBN (39 mg, 0.02 mmol, 0.3 equiv). The mixture was then
degassed, heated at 80 ꢁC, and a degassed solution of Bu3SnH (320
mL,
133.7, 130.4, 130.3, 130.2, 130.1, 129.4, 129.2, 128.9, 128.8, 122.6 (dd,
J¼261.2, 254.2 Hz), 79.3 (d, J¼5.1 Hz), 78.7 (t, J¼3.0 Hz), 76.3, 76.0,
75.8, 75.6, 74.6 (d, J¼7.0 Hz), 43.8 (t, J¼23.7 Hz), 9.6 (d, J¼5.2 Hz). IR
(neat) nmax 2982, 1760, 1729, 1602 cmꢀ1. MS (ESIþ): m/z¼858.87
([2MþNa]þ). Anal. Calcd for C22H20F2O6: C, 63.16; H, 4.82. Found: C,
63.20; H, 4.79.
1.20 mmol, 1.5 equiv) in t-BuOH (15 mL) was added dropwise via
a syringe pump over 45 min. AIBN (39 mg, 0.02 mmol, 0.3 equiv) was
added every 30 min until total consumption of the starting material
(followed by NMR 19F), usually within 2 h. The solvent was then
evaporated and the crude residue was purified by flash chromatog-
raphy using cyclohexane/AcOEt (95:5 then 9:1) as eluent to afford the
pure (2S,3R,4R,5S) (20b) and the pure (2S,3R,4R,5R) (20a) dia-
stereomers, and a mixture of both (70 mg, 85 mg and 25 mg, re-
spectively, 89% overall) as pale yellow oils. Compound 20a: Rf¼0.30
4.12. (2R,3S,4R,5R)-1,1-Difluoro-2,3,4-tri(O-acetyl)-5-
methylcyclopentane-2,3,4-triol (23)
The same procedure was applied to 19 (100 mg, 0.22 mmol). Pu-
rification by column chromatography using cyclohexane/AcOEt (95:5
then 9:1) as eluent afforded the pure (2R,3S,4R,5R) diastereomer 23
and a mixture of the (2R,3S,4R,5R) and (2R,3S,4R,5S) diastereomers
(16 mg and 30 mg, respectively, 70% overall) as pale yellow oils.
(20% AcOEt in cyclohexane). [
a
]
þ15.4 (c 1.2, CHCl3). 1H NMR
D
(300 MHz, CDCl3)
d
5.32 (d, J¼9.4 Hz, 1H), 4.52–4.46 (m, 1H), 4.30–
4.23 (m, 1H), 2.53–2.33 (m, 1H), 2.15 (s, 3H), 1.51 (s, 3H), 1.29 (s, 3H),
1.19 (d, J¼7.1 Hz, 3H). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ106.6
Rf¼0.31 (20% EtOAc in cyclohexane). [
a
]
D þ6.1 (c 1.8, CHCl3). 1H NMR
(dt, J¼237.2, 8.1 Hz,1F), ꢀ122.9 (dtt, J¼237.4,16.5, 2.8 Hz,1F).13C NMR
(300 MHz, CDCl3)
d
5.25–5.17 (m, 2H), 4.94 (dd, J¼9.5, 5.7 Hz, 1H),
(75.5 MHz, CDCl3)
d
169.6, 126.4 (dd, J¼262.2, 256.4 Hz), 113.3, 81.5
2.56–2.35 (m, 1H), 2.15 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H), 1.17 (d,
(d, J¼6.9 Hz), 80.7 (d, J¼6.3 Hz), 78.0 (dd, J¼27.6, 17.8 Hz), 44.8
(t, J¼22.0 Hz), 27.1, 24.9, 20.9, 10.3 (d, J¼5.7 Hz). IR (neat) nmax 3490,
2986, 2941, 1761 cmꢀ1. MS (ESIþ): m/z¼268.1 ([MþH2O]þ). Anal.
Calcd for C12H14F2O3Se: C, 52.80; H, 6.44. Found: C, 52.67; H, 6.51.
J¼6.91 Hz, 3H). 19F NMR (282.5 MHz, CDCl3)
d
ꢀ111.6 (ddd, J¼243.8,
19.7,11.9 Hz,1F), ꢀ112.9 (dt, J¼244.0, 3.3 Hz,1F). 13C NMR (75.5 MHz,
CDCl3)
d
170.6,170.3,169.4,125.9 (t, J¼297.4 Hz), 76.5, 76.2, 75.9, 75.6,
75.5, 43.3 (t, J¼23.6 Hz), 20.8, 20.7, 20.5, 9.0 (d, J¼4.9 Hz). IR (neat)
Compound 20b: Rf¼0.20 (20% AcOEt in cyclohexane). [
a
]
ꢀ15.2
nmax 3486, 2947,1756 cmꢀ1. MS (ESIþ): m/z¼318.2 ([MþNa]þ), 332.07
D

3970
G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
([MþK]þ). HRMS (CIþ) calcd for C12H17F2O6 ([MþH]þ) m/z 295.0993,
temperature and the mixture was extracted with AcOEt (3ꢂ5 mL).
The combined organic layers were washed with water (4ꢂ10 mL)
then dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude residue was then purified by flash chromatog-
raphy using cyclohexane/AcOEt (95:05 to 90:10) as eluent to afford
the desired product as an unseparable mixture of diastereomers
(157 mg, 52%, dr¼83:17). Only the analytical data of the major
(RS,2S,3R,4R) diastereomer 27 are provided. Rf¼0.40 (30% EtOAc in
found 295.1004.
4.13. (2R,3S,4R,5R)-1,1-Difluoro-5-methylcyclopentane-2,3,4-
triol (24)
The same procedure was applied to 13 (100 mg; 0.31 mmol).
Purification by column chromatography using CH2Cl2/MeOH (98:2)
as eluent afforded the desired product (27 mg, 52%) as an unsepar-
able mixture of diastereomers and as a colorless oil. Only the ana-
lytical data of the major (2R,3S,4R,5R) diastereomer 24 are provided.
cyclohexane). [
a
]
ꢀ62.0 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3)
D
d
7.58 (d, J¼7.0 Hz, 2H), 7.34–7.15 (m, 13H), 6.05–5.94 (ddd, J¼18.6,
10.4, 8.3 Hz, 1H), 5.29–5.14 (m, 2H), 5.01 (d, J¼7.1 Hz, 1H), 4.67
(d, J¼12.1 Hz, 1H), 4.47 (t, J¼12.1 Hz, 2H), 4.18–4.14 (m, 2H), 4.02–3.91
(m, 1H), 3.77 (t, J¼4.5 Hz, 1H), 0.96 (s, 9H). 19F NMR (282.5 MHz,
Rf¼0.23 (10% MeOH in CH2Cl2). 1H NMR (300 MHz, CD3OD)
d 3.73–
3.66 (m,1H), 3.63–3.58 (m,1H), 3.35–3.26 (m,1H), 2.14–1.92 (m,1H),
1.09 (d, J¼7.1 Hz, 3H). 19F NMR (282.5 MHz, CD3OD)
d
ꢀ108.86 (dt,
CDCl3)
d
ꢀ74.3 (dd, J¼197.7, 11.4 Hz,1F), ꢀ75.4 (dd, J 197.7, ¼12.4 Hz,
¼
J¼226.1, 9.6 Hz, 1F), ꢀ110.21 (dt, J¼277.1, 15.0 Hz, 1F). 13C NMR
1F). 13C NMR (75.5 MHz, CDCl3)
d 137.3, 134.7, 129.2, 128.6, 128.5,
(75.5 MHz, CD3OD)
d
124.7 (dd, J¼256.4, 254.2 Hz), 82.7 (dd, J¼2.8,
128.4, 126.8 (t, J¼301.0 Hz), 124.3, 120.3, 82.4, 78.8, 73.1, 71.1, 62.5
(t, J¼12.6 Hz), 56.7, 22.6. IR (neat) nmax 3296, 3031, 2868, 1216,
1173 cmꢀ1. MS (ESIþ) m/z¼608.13 ([MþH]þ). HRMS (CIþ) calcd for
C30H36F2NO3SSe ([MþH]þ) m/z 608.1549, found 608.1552.
2.6 Hz), 82.0, 79.6, 78.8 (d, J¼5.3 Hz), 78.3 (dd, J¼4.1, 3.1 Hz), 45.8
(t, J¼22.1 Hz),10.1 (dd, J¼5.7, 2.7 Hz). IR (neat) nmax 3292, 2928, 2632,
2537, 1728, 1585 cmꢀ1. MS (ESIþ): m/z¼186.23 ([MþH2O] þ). Anal.
Calcd for C6H10F2O3: C, 42.86; H, 5.99. Found: C, 42.43; H, 5.94.
4.16. (SS,2R,3R,4R)-3,4-Bis(benzyloxy)-2-tert-
butanesulfinamido-1,1-difluoro-1-phenylselanyl-
hex-5-ene (31)
4.14. (RS)- and (SS)-N-[(2R,3R)-2,3-Bis(benzyloxy)pent-4-
enylidene]-tert-butanesulfinamide (26 and 30)
To a solution of aldehyde 25 (317 mg, 1.07 mmol) and Ti(OEt)4
(0.45 mL, 2.14 mmol, 2 equiv) in 5 mL of anhydrous THF was added
(R) or (S)-2-methyl-2-propanesulfinamide (130 mg, 1.07 mmol,
1 equiv) and the mixture was refluxed for 1 h. Saturated aqueous
NaCl (5 mL) was then added under vigorous stirring, and the sus-
pension formed was filtered through Celite and washed with
AcOEt. The filtrate was then washed with 10 mL of saturated
aqueous NaCl and the aqueous layer extracted with AcOEt. The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. The crude residue was then
purified by flash chromatography (cyclohexane/AcOEt 95:5 then
90:10) to afford the desired product (362 mg, 85% for 26, 345 mg,
The same procedure was applied to 30 (200 mg; 0.50 mmol).
Purification by column chromatography using cyclohexane/AcOEt
(95:05 then 90:10) as eluent afforded the desired product 31
(219 mg, 72%, dr >98:02). Rf¼0.52 (30% EtOAc in cyclohexane). [
a]
D
þ9.3 (c 1.2, CHCl3). 1H NMR (300 MHz, CDCl3)
d
7.56 (d, J¼8.0 Hz,
2H), 7.34–7.15 (m, 13H), 5.67–5.63 (m, 2H), 5.42–5.38 (m, 1H), 5.04
(d, J¼10.5 Hz, 1H), 4.69 (d, J¼10.5 Hz, 1H), 4.63 (d, J¼8.1 Hz, 1H),
4.52 (d, J¼11.1 Hz, 1H), 4.39 (d, J¼11.1 Hz, 1H), 4.32 (m, 1H), 3.95–
3.92 (m, 1H), 3.89–3.79 (m, 1H), 1.21 (s, 9H). 19F NMR (282.5 MHz,
CDCl3)
d
ꢀ76.0 (dd, J¼197.8, 11.3 Hz, 1F), ꢀ77.0 (dd, J¼197.8, 12.4 Hz,
1F). 13C NMR (75.5 MHz, CDCl3)
d
138.4, 137.3, 134.3, 129.2, 128.3,
127.3 (t, J¼300.0 Hz), 122.9, 83.6, 77.0, 75.1, 71.3, 62.1 (t, J¼23.8 Hz),
57.1, 22.8. IR (neat) nmax 3306, 2958, 2868, 1255, 1179 cmꢀ1. MS
(ESIþ) m/z¼608.13 ([MþH]þ). HRMS (CIþ) calcd for C30H36F2NO3SSe
([MþH]þ) m/z 608.1548, found 608.1544.
81% for 30). Compound 26: Rf¼0.48 (5% EtOAc in cyclohexane). [
a]
D
ꢀ189.7 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3)
8.03 (d, J¼5.1 Hz,
d
1H), 7.40–7.20 (m, 10H), 5.93–5.84 (ddd, J¼17.5, 10.1, 7.4 Hz, 1H),
5.39 (d, J¼4.1 Hz, 1H), 5.33 (s, 1H), 4.73 (d, J¼12.1 Hz, 1H), 4.63
(d, J¼11.9 Hz, 1H), 4.55 (d, J¼12.1 Hz, 1H), 4.42 (d, J¼11.9 Hz, 1H),
4.33 (t, J¼5.1 Hz, 1H), 4.12 (t, J¼6.4 Hz, 1H), 1.17 (s, 9H). 13C NMR
4.17. (RS,2S,3R,4R,5R)-3,4-Bis(benzyloxy)-2-tert-butane-
sulfinamido-1,1-difluoro-5-methylcyclopentane (29)
(75.5 MHz, CDCl3)
d 167.0, 138.1, 137.8, 134.1, 128.8, 128.2, 128.1,
127.9, 120.2, 81.6, 80.4, 72.7, 71.0, 57.9, 22.2. IR (neat) nmax 3030,
2866, 1622, 1207 cmꢀ1. MS (ESIþ) m/z¼400.13 ([MþH]þ), 417.07
([MþH2O]þ). Anal. Calcd for C23H29NO3S: C, 69.14; H, 7.32; N, 3.51.
Found: C, 69.16; H, 7.25; N, 3.68. Compound 30: Rf¼0.46 (5% EtOAc
To a degassed solution of 27 (100 mg, 0.165 mmol) and AIBN
(8.2 mg, 0.05 mmol, 0.3 equiv) in 4 mL of t-BuOH was added over
1 h under reflux a degassed solution of Bu3SnH (70 mL, 0.247 mmol,
1.5 equiv) in 2 mL of t-BuOH. AIBN (0.3 equiv) was added each
30 min until total consumption of the starting material (followed
by 19F NMR). The solvent was then evaporated and the crude res-
idue obtained was purified by flash chromatography (cyclohexane/
AcOEt 95:5 to 80:20) to afford the desired product (46 mg, 72%) as
a colorless oil and as a mixture of diastereomers. Rf¼0.52 (30%
in cyclohexane). [
a]
D þ77.4 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3)
d
8.06 (d, J¼4.7 Hz, 1H), 7.33–7.18 (m, 10H), 5.92–5.80 (ddd, J¼18.2,
10.6, 7.5 Hz, 1H), 5.28 (d, J¼3.0 Hz, 1H), 5.24 (d, J¼10.7 Hz, 1H), 4.71
(d, J¼12.0 Hz, 1H), 4.60 (d, J¼12.1 Hz, 1H), 4.48 (d, J¼12.1 Hz, 1H),
4.34 (d, J¼12.0 Hz, 1H), 4.18 (t, J¼4.7 Hz, 1H), 4.02 (t, J¼4.7 Hz, 1H),
1.15 (s, 9H). 13C NMR (75.5 MHz, CDCl3)
d
168.3, 137.7, 137.4, 134.2,
AcOEt in cyclohexane). 1H NMR (300 MHz, CDCl3)
d 7.43–7.23 (m,
128.4, 120.0, 81.1, 80.9, 72.7, 70.7, 56.9, 22.6. IR (neat) nmax 3031,
2928, 1625, 1274 cmꢀ1. MS (ESIþ) m/z¼400.13 ([MþH]þ), 417.07
([MþH2O]þ). Anal. Calcd for C23H29NO3S: C, 69.14; H, 7.32; N, 3.51.
Found: C, 69.12; H, 7.27; N, 3.45.
10H), 4.75 (d, J¼18.8 Hz, 1H), 4.71 (d, J¼18.8 Hz, 1H0), 4.59–4.48 (m,
2Hþ2H0), 4.41 (d, J¼18.8 Hz, 1H), 4.36 (d, J¼18.8 Hz, 1H0), 4.14–3.97
(m, 3Hþ3H0), 3.70 (d, J¼6.1 Hz, 1H0), 3.53 (d, J¼7.2 Hz, 1H), 2.58–
2.49 (m, 1H0), 2.32–2.06 (m, 1H), 1.25 (s, 9Hþ9H0), 1.16 (d, J¼7.1 Hz,
3H), 1.06 (d, J¼7.1 Hz, 3H0). 19F NMR (282.5 MHz, CDCl3)
ꢀ101.3 (d,
d
4.15. (RS,2S,3R,4R)-3,4-Bis(benzyloxy)-2-tert-
butanesulfinamido-1,1-difluoro-1-phenylselanyl-
hex-5-ene (27)
J¼250.8 Hz), ꢀ105.8 (d, J¼235.8 Hz), ꢀ106.6 (d, J¼234.1 Hz), ꢀ120.3
(d, J¼232.7 Hz). 13C NMR (75.5 MHz, CDCl3)
d 136.6, 136.5, 136.3,
136.2, 128.9, 128.8, 128.7, 128.6, 128.4 (2C), 128.2 (2C), 128.0, 127.9,
126.1 (t, J¼256.1 Hz), 86.9 (d, J¼7.2 Hz), 80.6, 80.5, 80.4, 80.3, 80.2,
80.0, 73.0 (2C), 72.4, 72.3, 61.6 (d, J¼19.1 Hz), 61.2 (d, J¼19.1 Hz),
60.8 (d, J¼19.1 Hz), 60.5 (d, J¼19.1 Hz), 56.8, 56.7, 43.7 (t, J¼21.8 Hz),
41.9 (t, J¼23.0 Hz), 22.8, 11.0 (d, J¼6.9 Hz), 7.3 (d, J¼7.4 Hz). MS
(ESIþ): m/z¼452.20 ([MþH]þ), 903.0 ([2MþH]þ). Anal. Calcd for
To a solution of 26 (200 mg, 0.50 mmol) and PhSeCF2TMS
(335 mg, 1.20 mmol, 2.4 equiv) in 4 mL of anhydrous DMF at ꢀ40 ꢁC
was added TBAT (270 mg, 0.50 mmol, 1 equiv). After 2 h stirring at
ꢀ40 ꢁC, saturated aqueous NH4Cl (4 mL) was added at this

G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
3971
C24H31F2NO3S: C, 63.83; H, 6.92; N, 3.10; S, 7.10. Found: C, 63.91; H,
7.26; N, 3.09; S, 6.78.
128.6 (2C),128.3, 127.9, 126.8 (t, J¼301.4 Hz),121.1, 81.1, 75.0, 71.1, 54.2
(dd, J¼24.7, 22.4 Hz), 23.5. IR (neat) nmax 3433, 3031, 2867,1689 cmꢀ1
.
MS (ESIþ) m/z¼562.80 ([MþH2O]þ), 546 ([MþH]þ). HRMS (CIþ) calcd
for C28H30F2NO3Se ([MþH]þ) m/z 546.1359, found 546.1363.
4.18. (SS,2S,3R,4R,5R)-3,4-Bis(benzyloxy)-2-tert-butane-
sulfinamido-1,1-difluoro-5-methylcyclopentane (33)
Acknowledgements
The same procedure was applied to 31 (100 mg, 0.165 mmol).
Purification by column chromatography using cyclohexane/AcOEt
(95:5 to 80:20) to afford 33 (50 mg, 78%) as a colorless oil and as
a mixture of diastereomers. Only the analytical data of the major
(SS,2S,3R,4R,5R) diastereomer 33 are provided. Rf¼0.19 (20% AcOEt in
We thank the Centre National de la Recherche Scientifique
´
(CNRS) and the Region Haute-Normandie for a PhD grant to G.F. We
also thank Dr. Pedro Lameiras, Sophie Guillard, and Pr. Hassan
Oulyadi (LRMN, COBRA UMR 6014, Mont Saint-Aignan, France) for
the NOESY experiments.
cyclohexane). 1H NMR (300 MHz, CDCl3)
d
7.48 (d, J¼7.8 Hz, 2H),
7.38–7.28 (m, 8H), 4.88 (d, J¼11.6 Hz,1H), 4.66 (d, J¼11.6 Hz,1H), 4.58
(s, 2H), 3.87–3.77 (m, 2H), 3.59–3.55 (m, 1H), 3.42 (d, J¼6.6 Hz, 1H),
2.38–2.23 (m, 1H), 1.22 (s, 9H), 1.14 (d, J¼7.9 Hz, 3H). 19F NMR
Supplementary data
(282.5 MHz, CDCl3)
d
ꢀ103.9 to ꢀ104.0þꢀ104.7 to ꢀ104.9 (m, 1F),
Copies of 1H, 19F, 13C NMR spectra for most compounds as well as
copies of NOESY spectra for 20a, 20b, 21, 23, and 29 are provided.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2010.03.079.
ꢀ109.8 (dt, J¼234.6, 8.6 Hz, 1F). 13C NMR (75.5 MHz, CDCl3)
d 137.9,
137.8, 128.8, 128.7, 128.4, 128.3, 128.2, 128.1, 128.0, 127.3, 124.8
(dd, J¼258.9, 253.3 Hz), 86.3 (d, J¼5.8 Hz), 85.6 (dd, J¼5.5, 2.6 Hz),
73.1, 72.6, 63.8 (dd, J¼26.6, 19.1 Hz), 57.0, 43.7 (dd, J¼23.0, 20.8 Hz),
22.7, 12.7 (dd, J¼6.5, 3.9 Hz). MS (ESIþ): m/z¼452.13 ([MþH]þ). Anal.
Calcd for C24H31F2NO3S: C, 63.83; H, 6.92; N, 3.10; S, 7.10. Found: C,
63.87; H, 6.88; N, 3.09; S, 7.01.
References and notes
1. (a) Mathe´, C.; Gosselin, G. Antiviral Res. 2006, 71, 276–281; (b) Matsuda, A.;
Sasaki, T. Cancer Sci. 2004, 95, 105–111.
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Academic: Dordrecht, 1998; (b) Crimmins, M. T. Tetrahedron 1998, 54, 9229–
9272; (c) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319–4348.
4.19. (2S,3R,4R)-3,4-Bis(benzyloxy)-1,1-difluoro-1-
phenylselanyl-2-acetamido-hex-5-ene (28)
3. (a) Meier, C.; Knispel, T.; Marquez, V. E.; Siddiqui, M. A.; De Clercq, E.; Balzarini,
J. J. Med. Chem. 1999, 42, 1615–1624; (b) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, Germany, 2004; (c) Wang, J.; Jin, Y.; Rapp, K.
L.; Bennett, M.; Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2005, 48, 3736–3748 and
references cited therein.
4. For the synthesis of fluorinated carbocyclic analogues of deoxypentofuranoses,
see: (a) Barth, F.; O-Yang, C. Tetrahedron Lett. 1991, 32, 5873–5876; (b) Arnone,
A.; Bravo, P.; Cavicchio, G.; Frigerio, M.; Viani, F. Tetrahedron 1992, 48, 8523–
8540; (c) Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. Org. Lett. 2004, 6, 4257–4259; (d)
Kumamoto, H.; Haraguchi, K.; Ida, M.; Nakamura, K. T.; Kitagawa, Y.; Hamasaki,
T.; Baba, M.; Matsubayashi, S. S.; Tanaka, H. Tetrahedron 2009, 65, 7630–7636.
5. For the synthesis of fluorinated carbocyclic analogues of hexopyranoses, see: (a)
Jiang, S.; Singh, G.; Batsanov, A. S. Tetrahedron: Asymmetry 2000, 11, 3873–3877;
To a solution of 27 (200 mg, 0.33 mmol) in 4.5 mL of anhydrous
MeOH was added HCl (4 M in dioxane, 83 mL, 1 equiv) every hour
until total consumption of the starting material. After concentration,
the crude residue (196 mg, 0.39 mmol) was dissolved in 10 mL of
anhydrous CH2Cl2 then Et3N (0.11 mL, 0.78 mmol, 2 equiv), DMAP
(6 mg, 0.05 mmol, 0.12 equiv), and Ac2O (0.073 mL, 0.78 mmol,
2 equiv) were added. After 1 h 30 min stirring at rt, water was added.
The aqueous layer was then extracted with CH2Cl2 and the combined
organics were washed with saturated aqueous NaCl, dried over
MgSO4, filtered, and concentrated under reduced pressure. The crude
residue was then purified by flash chromatography (cyclohexane/
AcOEt 95:05 to 80:20) to afford 28 (161 mg, 90% overall). Rf¼0.42
´
´
(b) Audouard, C.; Fawcett, J.; Griffith, G. A.; Kerouredan, E.; Miah, A.; Percy, J. M.;
Yang, H. Org. Lett. 2004, 6, 4269–4272; (c) Deleuze, A.; Menozzi, C.; Sollogoub, M.;
Sinay¨, P. Angew. Chem., Int. Ed. 2004, 43, 6680–6683; (d) Sardinha, J.; Guieu, S.;
Deleuze, A.; Ferna´ndez-Alonso, M. C.; Rauter, A. P.; Sinay¨, P.; Marrot, J.; Jime´nez-
Barbero, J.; Sollogoub, M. Carbohydr. Res. 2007, 342, 1689–1703; (e) Sardinha, J.;
Rauter, A. P.; Sollogoub, M. Tetrahedron Lett. 2008, 49, 5548–5550.
(30% EtOAc in cyclohexane). 1H NMR (300 MHz, CDCl3)
d 7.65
(d, J¼7.9 Hz, 2H), 7.37–7.16 (m, 13H), 7.02 (d, J¼9.2 Hz,1H), 5.90 (ddd,
J¼18.2, 10.1, 8.0 Hz, 1H), 5.29–5.13 (m, 2H), 5.10–4.91 (m, 1H), 4.54
(d, J¼11.7 Hz, 1H), 4.43 (d, J¼10.6 Hz, 1H), 4.28 (d, J¼10.3 Hz, 1H), 4.14
(d, J¼10.3 Hz, 2H), 3.65 (s, 1H), 1.68 (s, 3H). 19F NMR (282.5 MHz,
6. (a) Moreno, B.; Quehen, C.; Rose-He´le`ne, M.; Leclerc, E.; Quirion, J.-C. Org. Lett.
2007, 9, 2477–2480; (b) Poulain, F.; Serre, A.-L.; Lalot, J.; Leclerc, E.; Quirion, J.-C.
J. Org. Chem. 2008, 73, 2435–2438; (c) Poulain, F.; Leclerc, E.; Quirion, J.-C.
Tetrahedron Lett. 2009, 50, 1803–1805 and references cited therein.
7. Fourrie`re, G.; Lalot, J.; Van Hijfte, N.; Quirion, J.-C.; Leclerc, E. Tetrahedron Lett.
2009, 50, 7048–7050.
CDCl3)
d
ꢀ77.0 (dd, J¼197.7, 7.2 Hz, 1F), ꢀ78.8 (dd, J¼197.7, 19.6 Hz,
1F).13C NMR (75.5 MHz, CDCl3)
d
171.1, 137.9, 137.5, 137.0, 135.4, 130.3,
8. Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849–7856.
129.7, 129.3, 128.9, 128.5, 124.6 (t, J¼300.4 Hz), 120.1, 83.7, 77.1, 72.9,
71.9, 55.0 (dd, J¼24.9, 20.7 Hz), 23.6. IR (neat) nmax 3397, 3031, 2868,
1686 cmꢀ1. MS (ESIþ) m/z¼562.80 ([MþH2O]þ), 546 ([MþH]þ). Anal.
Calcd for C28H29F2NO3Se: C, 61.76; H, 5.37; N, 2.57. Found: C, 61.74; H,
5.23; N, 2.53.
9. For the addition to aromatic or poorly functionnalized aliphatic aldehydes, see:
(a) Qin, Y.-Y.; Qiu, X.-L.; Yang, Y.-Y.; Meng, W.-D.; Qing, F.-L. J. Org. Chem. 2005,
70, 9040–9043; (b) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. J. Fluorine
Chem. 2005, 126, 529–534; (c) Sugimoto, H.; Nakamura, S.; Shibata, Y.; Shibata,
N.; Toru, T. Tetrahedron Lett. 2006, 47, 1337–1340; (d) Mizuta, S.; Shibata, N.;
Ogawa, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Chem. Commun. 2006, 2575–
2577; (e) Pohmakotr, M.; Boonkitpattarakul, K.; Ieawsuwan, W.; Jarussophon,
S.; Duangdee, N.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2006, 62, 5973–5985;
(f) Pohmakotr, M.; Panichakul, D.; Tuchinda, P.; Reutrakul, V. Tetrahedron 2007,
63, 9429–9436.
4.20. (2R,3R,4R)-3,4-Bis(benzyloxy)-1,1-difluoro-1-
phenylselanyl-2-acetamido-hex-5-ene (32)
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The same procedure was applied to 31 (200 mg, 0.33 mmol).
Purification by column chromatography using cyclohexane/AcOEt
(95:05 to 80:20) afforded 32 (152 mg, 85% overall). Rf¼0.28 (30%
11. Aldehyde 9 was prepared according to a procedure similar to 4 and 5.
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V.; Arnone, A.; Bravo, P.; Viani, F. Tetrahedron 1991, 47, 9439–9448; (b) Mor-
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Crucianelli, F. J. Org. Chem. 1994, 59, 3459–3466; (e) Qin, Y.-Y.; Yang, Y.-Y.; Qiu,
X.-L.; Qing, F.-L. Synthesis 2006, 1475–1479; (f) Li, Y.; Hu, J. Angew. Chem., Int. Ed.
2007, 46, 2489–2492; (g) Bootwicha, T.; Panichakul, D.; Kuhakarn, C.; Prabpai,
S.; Kongsaerere, P.; Tuchinda, P.; Reutrakul, V.; Pohmakotr, M. J. Org. Chem.
2009, 74, 3798–3805.
EtOAc in cyclohexane). 1H NMR (300 MHz, CDCl3)
d
7.63 (d, J¼7.0 Hz,
2H), 7.34–7.14 (m, 13H), 6.23 (d, J¼9.6 Hz,1H), 5.72 (ddd, J¼15.6,10.0,
7.6 Hz, 1H), 5.40 (d, J¼1.9 Hz, 1H), 5.34 (d, J¼3.3 Hz, 1H), 4.88
(d, J¼10.2 Hz, 1H), 4.81 (dt, J¼16.4, 7.4 Hz, 1H), 4.65 (dd, J¼12.8,
10.3 Hz, 2H), 4.39 (d, J¼11.8 Hz, 1H), 4.08 (d, J¼7.6 Hz, 1H), 3.87
(t, J¼7.5 Hz,1H), 2.01 (s, 3H).19F NMR (282.5 MHz, CDCl3)
ꢀ76.2 (dd,
d
J¼197.7, 8.2 Hz, 1F), ꢀ78.4 (dd, J¼197.7, 16.5 Hz, 1F). 13C NMR
(75.5 MHz, CDCl3) d 169.9,138.4,137.8,137.5,134.0,129.7,129.4,128.7,

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G. Fourrie`re et al. / Tetrahedron 66 (2010) 3963–3972
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´
´
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